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Intravascular delivery of nucleic acid

a nucleic acid and intravascular technology, applied in the direction of peptide/protein ingredients, non-active genetic ingredients, genetic material ingredients, etc., can solve the problem of not being readily clinically viable, and achieve the effect of increasing the permeability of the vessel

Inactive Publication Date: 2006-03-21
ARROWHEAD MADISON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]In a preferred embodiment, the process further comprises administration of at least one anesthetic or analgesic drug or adjuvant. Administration of anesthetics or analgesic lessens potential discomfort or pain experienced by the mammal during or after the procedure. Examples of such drugs lidocaine, NSAIDs, clonidine, ketamine, neuromuscular blockers, and immunsuppressants.
[0010]In another embodiment, a process is described for delivering a polynucleotide-containing non-viral complex into a parenchymal cell of a mammal, comprising: making the polynucleotide-compound complex wherein the compound is selected from the group consisting of amphipathic compounds, polymers and non-viral vectors, inserting the polynucleotide into a mammalian vessel and increasing the permeability of the vessel thereby delivering the polynucleotide to the parenchymal cell.

Problems solved by technology

A basic challenge in gene therapy is to develop approaches for delivering genetic information to cells in vivo in a way that is efficient and safe.
While intra-arterial delivery of polynucleotides to limb skeletal muscle cells has proven to be effective, the procedure is not readily clinically viable.

Method used

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Examples

Experimental program
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example 1

Reporter Polynucleotides

[0100]The pCI-Luc-K expression vector was generated by ligating the CMV enhancer / promoter (pCI mammalian expression vector; Promega, Madison, Wis.) to the expression cassette of the firefly luciferase reporter gene (pSP-luc+ expression vector—Promega) and replacing the ampicillin antibiotic resistance gene with the kanamycin antibiotic resistance gene. pCI-LacZ is similar to pCI-Luc-K and contained the β-galactosidase reporter gene under control of a cytomegalovirus enhancer / promoter. pCMV-hSEAP expresses human secreted alkaline phosphatase, hSEAP, from the cytomegalovirus enhancer / promoter. pMIR48 contains the firefly luciferase gene under control of the cytomegalovirus enhancer / promoter.

[0101]Reporter or marker genes, such as the genes for luciferase and β-galactosidase, serve as useful paradigms for expression of intracellular proteins in general. Similarly, reporter or marker genes, such as secreted alkaline phosphatase (SEAP) serve as useful paradigms fo...

example 2

Intravascular Injections of DNA / Labile Polymer Complexes

[0103]A. Synthesis of L-cystine-1,4-bis(3-aminopropyl)piperazine copolymer (M66): To a solution of L-cystine (1 g,4.2 mmol, Aldrich Chemical Company) in acetone (10 ml) and water (10 ml) was added 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.5 g,10 mmol, Aldrich) and triethylamine (1.4 ml, 10 mmol, Aldrich) to yield N,N′-Bis(t-BOC)-L-cystine. The reaction was allowed to stir overnight at room temperature. The water and acetone was then removed by rotary evaporation resulting in a yellow solid. The diBOC compound was then isolated by flash chromatography on silica gel eluting with ethyl acetate 0.1% acetic acid. To a solution of N,N′-Bis(t-BOC)-L-cystine (85 mg, 0.15 mmol) in ethyl acetate (20 ml) was added N,N′-dicyclohexylcarbodiimide (108 mg, 0.5 mmol) and N-hyroxysuccinimide (60 mg, 0.5 mmol). After 2 hr, the solution was filtered through a cotton plug and 1,4-bis(3-aminopropyl)piperazine (54 μL, 0.25 mmol) was ad...

example 3

[0110]A. Synthesis of 5,5′-Dithiobis(2-nitrobenzoic acid)Tetraethylenepentamine Copolymer (M57): Tetraethylenepentamine (3.2 μL, 0.017 mmol, Aldrich) was taken up in 1.0 ml dichloromethane and HCl (1 ml, 1 M in Et2O, Aldrich) was added Et2O was added and the resulting HCl salt was collected by filtration. The salt was taken up in 1 ml DMF and 5,5′-dithiobis[succinimidyl(2-nitrobenzoate)] (10 mg, 0.017 mmol) was added. The resulting solution was heated to 80° C. and diisopropylethylamine (15 μL, 0.085 mmol, Aldrich) was added dropwise. After 16 hr, the solution was cooled, diluted with 3 ml H2O, and dialyzed in 12,000–14,000 MW cutoff tubing against water (2×2 L) for 24 h. The solution was then removed from dialysis tubing and dried by lyophilization to yield 5.8 mg (62%) of 5,5′-dithiobis(2-nitrobenzoic acid)—tetraethylenepentamine copolymer.

[0111]B. Mouse Tail Vein Injections of pDNA (pCI Luc) / M57 polymer Complexes:

[0112]Complexes were prepared as follows:[0113]Complex I: pDNA (pCI...

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Abstract

Disclosed is a process for providing for expression of an exogenous nucleic acid in an extravascular parenchymal cell of a mammal. The nucleic acid is inserted into a vessel of a mammal and the permeability of the vessel is increased. Increasing permeability of the vessel allows delivery of the nucleic acid to an extravascular parenchymal cell.

Description

CROSS-REFERENCE TO RELATES APPLICATIONS[0001]This application is a continuation-in-part of application Ser. No. 10 / 085,378, filed Feb. 27, 2002 now U.S. Pat. No. 6,897,068 a continuation-in-part of application Ser. No. 09 / 707,000, filed Nov. 6, 2000, and a continuation-in-part of application Ser. No. 10 / 855,175, filed May 27, 2004, application Ser. No. 10 / 085,378 is a continuation-in-part of application Ser. No. 09 / 450,315, filed Nov. 29, 1999, issued as U.S. Pat. No. 6,379,966, which claims the benefit of U.S. Provisional Applications No. 60 / 121,730, filed Feb. 26, 1999, and 60 / 146,564, filed Jul. 30, 1999, application Ser. No. 09 / 707,000 claims the benefit of U.S. Provisional Application No. 60 / 163,719, filed Nov. 5, 1999, and application Ser. No. 10 / 855,175 claims the benefit of U.S. Provisional Applications No. 60 / 473,654 filed on May 28, 2003 and 60 / 500,211 filed Sep. 4, 2003.FIELD OF THE INVENTION[0002]The invention relates to compounds and methods for use in biologic systems....

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C12N15/88A61K38/12A61K48/00C12N15/87
CPCA61K48/0008A61K48/0041A61K48/0083C12N15/87A61K48/0075A61K48/00A61K38/00
Inventor WOLFF, JON A.BUDKER, VLADIMIR G.HAGSTROM, JAMES E.HEGGE, JULIAHERWEIJER, HANS
Owner ARROWHEAD MADISON
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